1. Field of the Invention
The present invention relates to certain bicyclic-pyrazole compounds, to pharmaceutical compositions thereof, and to the use of these bicyclic-pyrazole compounds or pharmaceutical compositions thereof in the treatment of certain diseases.
2. Discussion of the Background
The insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is a member of the insulin receptor subfamily of RTKs. IGF-1R has a relatively ubiquitous pattern of tissue expression, and consists of two alpha chains, which are extracellular and contain ligand binding function, and two beta chains, which span the cell membrane and contain the intracellular kinase domains. The mature receptor consists of a disulphide-linked heterodimer of two pairs of alpha/beta subunits, resulting in an (alpha/beta)2 complex. IGF-1R is able to bind and be activated by the ligands insulin-like growth factor-1 and -2 (IGF-1 and IGF-2). Insulin will also activate IGF-1R, but only at supraphysiological concentrations (i.e. in the range of circa 100 nanoM-1 microM).
IGF-1 and IGF-2 are circulating growth factors which mediate many of the effects of Growth Hormone (GH), and which therefore have important roles in foetal and post-natal growth and metabolism. IGF-1R, like several other RTKs such as the EGF and PDGF receptor families, has potent mitogenic, anti-apoptotic and transforming activity in a wide range of cell types. Notably, it directly activates at least two major cell signaling pathways, the ras/MAPK pathway, through recruitment of SHC, and the PI-3 kinase/AKT (PKB) pathway, through recruitment and phosphorylation of the IRS adapter proteins.
There exist several lines of evidence suggesting that IGF-1R signaling can contribute to tumorigenesis, and that interfering with IGF-1R function represents a valid therapeutic option in cancer. IGF-1R signaling can promote tumorigenesis through multiple mechanisms. Aside from being mitogenic for most, if not all, cells which express IGF-1R promote cell survival and inhibit apoptosis through activation of the PI-3K/AKT and ras/MAPK, as well as other signaling pathways, depending on cellular context.
Various experimental strategies have demonstrated that interference with IGF-1R function can result in anti-tumor effects in a wide range of tumor cell types. Low molecular weight, selective inhibitors of IGF-1R kinase activity have also been described and these agents inhibit the in vitro and in vivo growth of a wide range of human tumor cells.
Since IGF-1R promotes cell proliferation, transformation, and protection from apoptosis in a wide range of cell types and in response to cooperation with diverse stimuli, it follows that inhibition of IGF-1R function might potentiate the effects of chemotherapeutic agents having diverse mechanisms of action. A blockade of IGF-1R function using the strategies described above, including selective IGF-1R kinase inhibitors, has been found to augment the in vitro, and/or in vivo activity of a wide range of agents including signal transduction inhibitors such as Gleevec, anti-EGFR and anti-HER2 blocking antibodies, cytotoxic agents such as adriamycin, doxorubicin, 5-FU, vinorelbine, and antihormonal therapy.
Aside from cancer, IGF-1R activity is also implicated in a wide range of pathophysiological processes in which inhibition of receptor activity could be expected to yield clinical benefit. These include, but are not limited to, acromegaly, conditions involving persistent inflammation and/or cell proliferation such as psoriasis and fibrotic lung disease, and benign prostatic hyperplasia. Reduction of IGF-1R signaling has also been associated with increased longevity in several animal models, potentially due to increased tolerance of oxidative stress, such as that which occurs during hyperoxia, and related settings could also be therapeutically targeted by inhibiting the receptor.
IGF-1R signaling provides angiogenic stimulus in many tissues, at least in part through stimulation of hypoxic responses, including upregulation of VEGF expression. Accordingly, systemic blockade of IGF-1R using a monoclonal antibody has been found to be an effective treatment in an animal model of diabetic retinopathy, a condition involving inappropriate VEGF expression. Similarly, IGF-1R function has also been strongly implicated in contributing to development of retinopathy of prematurity as well as in age-related macular degeneration. There is also evidence that IGF-1 contributes to vascular neointimal formation, and to atherosclerotic processes.
Thus, IGFs/IGF-1R play a significant role in tumorigenic processes in a wide range of human tumors, and inhibition of IGF-1R function through approaches that include inhibitors of IGF-1R kinase activity could be expected to yield therapeutic benefit, either alone or in combination with many agents. Such therapy could be extended to several other pathologies which involve inappropriate IGF-1R activity. Accordingly, there is a need for new compounds that can inhibit IGF-1R kinase activity.